VALD-3 Induces GSDME-Dependent Pyroptosis via ROS/JNK/Bax Pathway in Triple-Negative Breast Cancer Cells

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited treatment options.
• Existing therapies for TNBC often lack specificity and efficacy, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the anticancer effects of VALD-3, a Schiff base ligand derivative, on breast cancer cells.
• To elucidate the mechanism of VALD-3-induced cell death, focusing on pyroptosis in TNBC.

Main Methods:

• VALD-3 treatment of TNBC and ER+ MCF-7 cells.
• Assessment of cell viability, pyroptotic features, reactive oxygen species (ROS) levels, JNK phosphorylation, and mitochondrial pathway activation.
• Analysis of caspase-3 activation and gasdermin E (GSDME) cleavage.

Main Results:

• VALD-3 exhibited potent cytotoxicity against TNBC cells, more so than ER+ MCF-7 cells.
• VALD-3 selectively induced pyroptosis in TNBC cells, characterized by cell swelling and inflammatory cytokine release.
• The mechanism involved increased ROS and JNK phosphorylation, leading to mitochondrial apoptosis pathway activation, caspase-3 activation, and GSDME-dependent pyroptosis.

Conclusions:

• VALD-3 effectively eradicates TNBC cells through GSDME-dependent pyroptosis.
• The ROS/JNK/Bax-mitochondrial apoptosis pathway is crucial for VALD-3-induced pyroptosis.
• VALD-3 represents a potential novel therapeutic agent for triple-negative breast cancer.